So let us get started with our material here. Here is the contemporary algorithm for the management of ER-positive, HER2-negative metastatic breast cancer. We still, for the large majority of patients, in the first line give endocrine therapy plus. Look a little bit at those data briefly, but that remains our first line standard of care for most patients.

Then it is at the time of progression on that first line, endocrine therapy plus CDK4/6 inhibitor, that we know we need to look at the genomics of a patient's profile, often doing ctDNA or plasma-based genotyping. That informs our second line therapy and beyond, as is depicted here. For the patients who have ESR1 mutations, mutations in the estrogen receptor itself, we have 2 FDA-approved single-agent oral serves, which are elacestrant and imlunestrant.

For patients who have PIK3CAm mutations, we have fulvestrant plus alpelisib regimen. Also, we have fulvestrant capivasertib regimen, so that green box should actually cover both therapies, PIK3CAm and AKT. If you have an AKT pathway alteration, which would include PIK3CAm and AKT and PTEN alterations, we have fulvestrant plus capivasertib. For the germline BRCA mutants, we have PARP inhibitors. Then, for the patients who we do not find any of these targetable alterations, generally our options are fulvestrant with a different CDK4/6 inhibitor, and we will look at those data, or fulvestrant with the mTOR inhibitor everolimus.

As we know, we can cycle through a number of different endocrine therapy options, and then at some point decide that endocrine therapy, either no more options exist or does not seem to be working anymore. At that point, we transition to chemotherapy or ADC, choosing between a first-line chemo or the first-line ADC T-DXd trastuzumab deruxtecan for anyone who is HER2 low or ultra low, and then go on to later-line chemotherapy and subsequent ADCs.

[00:07:55]

Summary Data for Frist-line Combinations of CDK4/6 Inhibitors and ET in HR+/HER2-Breast Cancer: PFS and OS

This is just the summary for the first line data for CDK4/6 inhibitor plus endocrine therapy backbone, which could be an aromatase inhibitor or fulvestrant. Usually, there are 3 FDA-approved CDK4/6 inhibitors in this setting palbociclib, ribociclib, and abemaciclib. Likely are all quite familiar with these, and as you can see in that median PFS line there, by and large, if you look at the median PFS for pretty much any of these regimens in the first line, they are all right around 2 years, right around 24 months.

In general, our patients, on average, are getting about 2 years out of their first line endocrine therapy plus CDK regimen. As you may know, some differences have come out in the overall survival. Statistical analyses of these trials where palbociclib has not consistently or has not shown at all an overall survival benefit and whereas that has been shown for abema and ribo, but the PFS again looks all about the same at about 2 years.

[00:09:05]

Continuing CDK4/6 Inhibition Beyond Progression in HR+/HER2-Breast Cancer: Randomized Trials

It is when you switch off of that first line CDK4/6 inhibitor with endocrine backbone that things get controversial and interesting, and we have lots of things to choose from, of course. One option that we frequently think about is whether we should switch our CDK4/6 inhibitor, but maintain that same global mechanism of action. There are 3 randomized trials that have looked at regimens continuing usually a different CDK4/6 inhibitor after progression on the first CDK4/6 inhibitor.

Those are the MAINTAIN trial, which was a phase III trial looking at using ribociclib. The PACE trial, using palbociclib, also a phase II trial. Then the postMONARCH trial, which was a randomized phase III trial looking at abema for patients who had progressed on a prior CDK4/6 inhibitor. I think of these 3 the most practice informing is the postMONARCH trial because it was a randomized phase III trial, and this did support that PFS was improved when you used fulvestrant abema compared to fulvestrant by itself, following a different CDK4/6 inhibitor in the first-line setting.

Fulvestrant abema is an evidence-based regimen to use here. The MAINTAIN trial of ribo with fulvestrant was also a positive trial, so ribo is also a reasonable option in a later line CDK setting, and the PACE trial, looking at palbociclib, was a negative trial. I would not typically use palbociclib as a second CDK4/6 inhibitor.

[00:10:38]

EMERALD: Elacestrant vs Investigator's Choice SoC ET in ER+/HER2- MBC

For patients, again, who have ESR1 mutations, we now have 2 FDA-approved oral SERDs. The first that was FDA approved was elacestrant on the basis of the EMERALD trial, which is shown here. This was a randomized phase III trial of elacestrant, the oral SERD, vs some endocrine therapy of the investigator's choice as a single agent. All of these patients had received a prior CDK4/6 inhibitor.

[00:11:09]

EMERALD: PFS After Previous ET + CDK4/6 Inhibitors

As shown here, this was a positive trial. We have known this for a couple of years now. If you looked in the ITT population, all the patients, overall elacestrant beat the standard of care as shown here. Where you really saw the most benefit come out, as shown on the right, was the patients who harbored an ESR1 mutation, where the median PFS went up from 1.9 to 3.8 months. On the basis of these data, this agent was FDA-approved specifically in tumors harboring an ESR1 mutation.

You can see, though, on the slide very clearly that, even though elacestrant did beat standard of care endocrine therapy here, almost 50% of patients are still experiencing progression at their first restaging, unfortunately. That is reflected in the fact that the median PFS is really not all that long, even on the elacestrant arm, only 3.8 months. It was a positive trial, but in all comers here, not a ton of clinical activity.

[00:12:07]

EMERALD Subgroup Analysis: PFS by Subgroup in ESR1m Patients with≥12 Mo of CDK4/6i

As shown on this slide here, there have been a lot of subsequent analyses trying to figure out, well, how can we pick out a subgroup of patients who will get more durable benefit out of single-agent elacestrant. What you can see here is that, specifically, looking in patients who had 12 or more months on their prior CDK4/6 inhibitor, that was a group where there seemed to be more durable and clinically meaningful benefit of the elacestrant.

You can see in that group there was an 8.6-month median PFS with elacestrant by itself, as opposed to, again, about 2 months with the standard of care endocrine therapy. The elacestrant was still beating out standard of care endocrine therapy in all of the subgroups shown. Patients with visceral disease, patients with PIK3CA mutations, TP53 mutations. Again, these are all patients who had at least 12 months of exposure to prior CDK. Generally, in my practice, I use a single-agent oral SERD for a patient who had a pretty durable response to their first line CDK4/6 based regimen.

[00:13:15]

EMBER-3 Update: Imlunestrant ≠ Abemaciclib vs SoC ET in ER+ HER2-Advanced Breast Cancer

The EMBER-3 trial was the trial that led to FDA approval of the other oral SERD that we now have available, called imlunestrant. Just to remind you, the design of this trial, this was, again, patients in the second line and beyond for ER-positive breast cancer. In this case, they were not all previously exposed to CDK4/6 inhibitor, but many were. In this case, there were 3 randomized arms. There was the oral SERD imlunestrant by itself, those imlunestrant with abemaciclib. Then there was a single-agent standard of care endocrine therapy control arm.

[00:13:52]

EMBER-3 Update (SABCS 2025): PFS(Primary Endpoint)

We have seen results of this trial before. This agent is FDA-approved. We saw updated results that continue to look promising, just at San Antonio Breast Cancer Symposium last month. You can see updated PFS results from San Antonio on the left here in the ESR1 mutant population imlunestrant the orange line is doing better than the control arm of standard of care endocrine therapy, with a median PFS of about 5.5 months in the imlunestrant arm. This is where the agent has its FDA approval and an ESR1 mutant population.

If you look at the right side of the slide, these are also updated results from San Antonio last month. This is the comparison of imlunestrant with or without abemaciclib. You can see that the imlunestrant abema doublet is winning here over the imlunestrant by itself. This is in the ITT population. These patients did not all have ESR1 mutations. Some did, some did not, and it seemed more convincing that this doublet of the oral SERD with a targeted agent was having activity regardless of ESR1 mutation status. That is, I think, a theme we will see a couple of times in this slide deck, we have seen in other trials. Unfortunately, at this point, we do not have any FDA approval for an oral SERD with a partner, a targeted agent, but we will see how these data evolves and hopefully potentially see that and be able to use it in the future.

[00:15:25]

EMBER-3 Update (SABCS 2025): PFS by Subgroups Imlunestrant + Abemaciclib vs Imlunestrant

These are, again, just some updated subgroup analyses from San Antonio looking at which subgroups seem to benefit from imlunestrant abema compared to imlunestrant by itself, and the CliffsNotes version of this slide is that it is better to use the doublet in all of the subgroups. If you had ESR1 mutation, if you did not, if you had a CDK4/6 inhibitor before, if you did not. If you had a PI3 kinase pathway mutation, imlunestrant abema was the winner here.

[00:15:56]

evERA Breast Cancer: Giredestrant + Everolimus vs Exemestane + Everolimus in ER+/HER2 ABC

On that same theme of using an oral SERD with a targeted partner, we also saw last year, actually at the ESMO conference in October, the results of this randomized phase III trial called evERA. In this trial, everybody got a doublet, which is helpful, I think. Again, a second line and beyond ER-positive metastatic breast cancer population, all of these patients that had a prior CDK4/6 inhibitor and were randomized to the oral SERD called giredestrant, combined with the mTOR inhibitor everolimus, or in the control arm as standard of care. Endocrine therapy of the investigator's choice, also with everolimus. This is doublet vs doublet, which I think is a very helpful comparison.

[00:16:47]

evERA Subgroup Analysis: PFS by Investigator in ESR1m and ITT Populations (Copprimary Endpoints)

This was a positive trial, and so the primary results again were presented at ESMO, but here are some of the updated results that were presented at San Antonio last month. If you look specifically in the ESR1 mutant population, then there was a significant improvement in median PFS with the giredestrant-based arm vs the other endocrine therapy backbone from 5.4 months up to basically 10 months.

Interestingly, and I think in a promising way, also, if you looked in the ITT population, some of whom had ESR1 mutations, some of whom did not, there also there was a significant improvement in median PFS from 5.5 months up to almost 9 months. Again, just continuing this theme that it does look like single-agent oral SERDs really work best in an ESR1 mutant population. If you combine them with a targeted agent, it may not matter so much anymore if you have an ESR1 mutation. We will have to see if this doublet regimen gets approved this year.

[00:17:53]

Multiple Heterogeneous Potential Mechanisms of Resistance to CDK4/6 Inhibitors

Just to sum up this first part, again, we are very committed and generally are using first line CDK4/6 inhibitor-based regimens. We know we have a really important unmet need in this very common metastatic breast cancer population to find treatment approaches that will work after that first-line CDK4/6 inhibitor stops working. Obviously, there is a lot of work going on and been years of efforts to understand resistance mechanisms to CDK4/6 inhibitors and how we can translate that biology into targeted and rational targeting of novel pathways in the second line. I think we still are not where we want to be in terms of understanding this biology and how to target it, but as you can see, we do understand a number of de novo and acquired resistance mechanisms to the first-line CDK4/6 inhibitor, and are still trying to develop targeted ways to approach those.

[00:18:53]

On that topic of new ways to think about endocrine-based regimens for this patient population, let us dive in to the mechanisms of PROTAC ER degraders. What does that exactly mean, and contrast that with other endocrine therapies in the next few minutes?

[00:19:12]

ESR1 Acquired Mutations: Resistance to AI

We have talked about ESR1 acquired mutations, and let us go over their prevalence and exactly what it means to have an ESR1 mutation in your tumor. On the left side of the slide here, you can see that dark blue circle is an androgen precursor. Under normal circumstances, the enzyme aromatase converts it into estrogen, and then the estrogen can enter the cancer cell, which is diagrammed here.

The estrogen can dock into that wild-type estrogen receptor, the purple ESR1 circle there. Then, when that happens, the estrogen receptor with the estrogen attached to it, they translocate into the nucleus of the cell, and they turn on all these different transcriptional programs through these estrogen responsive elements, or ERS, and all these different transcriptional programs, tell the cell to proliferate and have all these cancer cell behaviors that we are always talking to our patients about. That is estrogen-dependent ESR1 activation.

The way that aromatase inhibitors work, as diagrammed there, is that if you inhibit that conversion of an androgen precursor into an estrogen, then you do not have estrogen present, and so this whole cascade cannot happen. On the right side of the slide, you can see that even here in the absence of estrogen, if you have a mutant estrogen receptor, a mutant ESR1, which is the gray blob that is misshapen there, then you no longer need that estrogen molecule to dock into the estrogen receptor in order to activate these transcriptional programs. In the presence of an ESR1 mutation, you get estrogen-independent ESR1 activation, and aromatase inhibitors do not work and do not make a difference anymore.

[00:21:05]

Mechanism of Action: AI, SERMs, SERDs, PROTACs

This slide is just a continuation looking at other mechanisms of other endocrine agents that we commonly use. In no treatment, we just talked about how that cascade works. The aromatase inhibitors are inhibiting that aromatase at the very top of the cascade here. The SERMs are selective estrogen receptor modulators, like tamoxifen, are competing with the estrogen and can bind to the estrogen receptor in place of the estrogen and shut down the estrogen receptor mediated transcriptional profiles in that way. The SERDs, selective estrogen receptor degraders, like elacestrant fulvestrant, imlunestrant, these work differently. Again, these bind to the estrogen receptor.

They bring about this conformational change in the estrogen receptor that ultimately lead it to be recognized by the cell as abnormal and lead to its degradation. SERDs do lead to estrogen receptor degradation as shown there, and as their name implies, but it is an indirect process by which the conformational change leads to the cell figuring out to degrade that estrogen receptor. PROTACs lead to estrogen receptor degradation, as shown here, but they do it via a different mechanism.

PROTAC stands for proteolysis targeting Chimera. What PROTACs do is that they have this shape as diagramed by that black circle and turquoise triangle. The PROTAC is engineered so that 1 end of the molecule looks like estrogen and can dock into the estrogen receptor. Then the other end of the molecule can dock into this ubiquitin ligase proteasome system that degrades proteins in the cell.

When the PROTAC, the ER targeted PROTAC, comes in contact with the estrogen receptor, it binds into that estrogen receptor and then, in a very direct and efficient way, recruits the proteolysis machinery of the cell. The ubiquitin ligase it comes directly to that estrogen receptor to degrade it. Both SERD and PROTAC are leading to estrogen receptor degradation, but it is a more direct, efficient process when the PROTAC is facilitating that.

[00:23:33]

ESR1 Mutations in Breast Cancer

ESR1 mutations in breast cancer, just to note about their prevalence, very uncommon in primary breast tumors. If you look in metastatic breast cancer that is been previously exposed to an aromatase inhibitor, as you can see in the table on the right, we end up seeing incidence of ESR1 mutation up to 30%, 40%, and in some cohorts even somewhat more than 40%.

[00:23:56]

Guidelines for ESR1 Mutations Testing

Also, just a reminder about ESR1 mutation testing guidelines that the ASCO guidelines do recommend testing for ESR1 mutations at recurrence or progression on the first line regimen, and blood-based ctDNA assays are actually preferred for doing this.

[00:24:14]

Rationale for Continued Targeting ERs Following Disease Progression

As we know in our clinical practice, we do see ongoing activity of endocrine agents and endocrine-based regimens, even after disease progression on an initial endocrine-based therapy like a CDK4/6 inhibitor. There is definitely clinical rationale for continuing targeting of the estrogen receptor following that disease progression.

[00:24:37]

PROTAC ER Degraders

Again, PROTAC ER degraders are a molecule that was developed to fill some of that void of how can we continue to target the estrogen receptor better? I went over how they differ from the oral SERDs or from any SERDs, and they have a number of other advantages, as shown here in oral formulation. Dr Nanda will go through their activity in ESR1 mutant breast cancer, and just this particularly efficient targeting of ER for degradation.

[00:25:08]

PROTAC ER Degraders vs Other ER Inhibitors

Again, if you look at these compared to other ER inhibitors, just the same - recapitulating what I have already said, maybe a hope to be more efficient and more targeted degradation and ability to be delivered orally, and also potentially target multiple different proteins of interest. You can imagine you do not have to have an ER binding site on 1 side of that molecule. You can target all other previously non-druggable targets. It is an exciting drug class in general.

[00:25:40]

Posttest Question 1

I will wrap up with that. I will bring us back to our 2 same pretest questions, but we will do the post-test version here. Which of the following most accurately describes the mechanism of action of PROTAC ER degraders? Is it that they bind free estrogen ligand, and therefore fewer molecules are available to bind the ER receptor? Do they bind and eliminate androgen, leading to estrogen production blockade? Do they compete with estrogen binding, facilitating ER internalization and degradation, or do they directly bind to the ER protein and facilitate recruitment of the protein degradation machinery?

Let us see the answers. I moved us over a little bit, which is what I was aiming to do. The final answer is the right 1 there. They bind that ER protein. Then, on the other end of the molecule, they bring that protein degradation machinery right up close to it. That is how they facilitate the degradation.